The proposed Center for Cancer Systems Biology, to be known as the Center for Complexity, Cooperation and Community in Cancer, is a joint effort by the systems biology and cancer biology communities at the University of California Irvine (UCI), as represented by two campus-wide research organizations, the Center for Complex Biological Systems and the UCI Cancer Research Institute. The center will tackle a variety of basic and fundamental questions about cancer systems, and why they are organized as they are. The premise underlying the research program of the center is that cancer cells proliferate and evolve in complex environments that have been highly selected for the robust control of growth and differentiation, and that the behaviors of cancer cells can only be fully understood in the context of the design principles that govern that control. As described in this proposal, the center will carry out three coordinated, team-oriented research projects on the role of context, cooperation and community in the initiation and progression of cancer. One project will leverage new observations from xenograft models of colon cancer to investigate non-genetic heterogeneity in solid tumors, both its origins and its relevance to tumor growth and response to therapy. A second project will investigate the cellular origins of melanoma, seeking to clarify the relationship between melanoma and the benign lesions (melanocytic nevi) that are driven by a common oncogenic event. This work will focus on interactions among melanocyte precursors, within the skin environment, and under conditions that promote progression from benign to malignant. The third project will focus on improving models of chronic myeloid leukemia (CML) and its treatment, taking into account interactions between hierarchical lineages, intercellular feedback, and dynamics. All three projects will combine mathematical modeling, genomics, and experimental manipulation of animal models. All three will be served by a core facility for investigating tumor cells at the single cell level, providing access to the latest in single-cell genomic, transcriptomic and other technologies. The center will also support short-term, interdisciplinary pilot projects initiated both by faculty and by trainees (graduate students and postdoctoral fellows), as well as a wide variety of outreach activities aimed at expanding and enriching the cancer systems biology community both within the university, in the larger scientific community, and among the public. Finally, the center will coordinate its research and outreach activities with those of other centers in the NCI Cancer Systems Biology network.